There is continuously a growing demand for enantiomerically pure amines in the pharmaceutical, agrochemical and fine chemicals industries. Over the past decade, there has been significant efforts directed towards developing procedures for asymmetric imine hydrogenations. Although many highly enantioselective chiral catalysts and catalytic processes are available for the asymmetric hydrogenation and transfer hydrogenation of C═C and C═O bonds, there are only a few widely applicable and feasible processes for effective reduction of the analogous C═N function of imines. The production of chiral amines via this methodology still represents a major challenge.
In 1997, B. R. James reviewed the preparation of chiral amines by homogeneous catalytic hydrogenation reactions involving metal complexes (James, Catalysis Today 1997, 37, 209-221). The review by James names several systems based on rhodium for the asymmetric hydrogenation of imines but they suffer from drawbacks, such as low enantioselectivity or severe reaction conditions. In U.S. Pat. No. 6,037,500, X. Zhang et al. disclosed the use of BICP, a chiral diphosphine ligand, on rhodium and iridium in the asymmetric hydrogenation of internal C═N bonds at 1000 psi H2 at room temperature to produce amines with e.e. ranging from 65 to 94%. Spindler and co-workers demonstrated the use of in situ generated iridium JOSIPHOS complexes for the enantioselective hydrogenation of imines (Spindler et al., Angew. Chem., Int. Ed. Engl., 1990, 29, 558; Blaser and Spindler, Topics in Catalysis, 1997, 4, 275). This process was subsequently modified and applied to the industrial production of the imine precursor to (S)-Metolachlor, a valuable agrochemical product, then for Ciba-Giegy, now for Novartis. The production of S-Metolachlor is an example of a large-scale industrial process that depends on the homogenous hydrogenation of a prochiral imine.
Buchwald and co-workers prepared and effectively employed various chiral ansa-titanocene complexes for both hydrogenation and hydrosilylation of imines (Willoughby and Buchwald, J. Am. Chem. Soc., 1992, 114, 7562; J. Am. Chem. Soc., 1994, 116, 8952 and 11703). The need to activate the catalyst by the addition of butyl-lithium and phenyl silane limits the scope and applicability of this process. This system also suffers from the drawback of being very oxygen and water sensitive.
A recent article by Tang and Zhang provides a comprehensive review on other advances in enantioselective hydrogenation of imines (Tang and Zhang, Chem. Rev. 2003, 103, 3029). These include several recent examples of the development and use of chiral complexes of rhodium (Buriak et al., Organometallics 1996, 15, 3161; Spindler et al., Adv. Synth. Catal. 2001, 343, 68), iridium (Bianchini et al., Organometallics 1998, 17, 3308; Kainz et al., J. Am. Chem. Soc., 1999, 121, 6421; Zhang et al., Angew. Chem. Int. Ed. Engl. 2001, 40, 3425) and palladium (Abe et al., Org. Lett. 2001, 3, 313) and their use for the asymmetric hydrogenation of various cyclic and acyclic imines.
Despite the reported successes of some of these catalytic hydrogenation processes for imines, there are certain significant drawbacks. These include high operating pressures (typically >50 bar H2), high catalyst loading and the use of expensive iridium- and rhodium-based systems. In addition, activity and/or enantioselectivity tends to be either low or highly substrate dependent, which in some cases necessitates the development of an entire catalytic system and process for only one substrate or a very closely related group of substrates.
Recently Rautenstrauch et al. reported the use of metal complexes with P—N bidentate ligands (WO 02/22526 A2) and PNNP tetradentate ligands (WO 02/40155 A1) in the catalytic hydrogenation of C═O and C═N carbon-heteroatom double bonds for the production of alcohols and amines, respectively. Noyori and coworkers have also described an efficient catalyst system generated from the complex Ru(η6-arene)(tosyldiamine)Cl for the asymmetric hydrogenation of imines by transferring hydrogen from triethylammonium formate (Noyori et al., Acc. Chem. Res. 1997, 30, 97-102).
Noyori and co-workers have pioneered the use of ruthenium complexes bearing a chelating diphosphine ligand (or two monodentate phosphines) and a chelating diamine ligand for the catalytic asymmetric hydrogenation of ketones. At least one and usually both of the chelating ligands are chiral. The various papers and patents of Noyori et al. have demonstrated the highly efficient reduction of various functionalised and unfunctionalised ketones using this class of catalysts. It was also demonstrated by Noyori and co-workers (Ohkuma et al., J. Am. Chem. Soc., 1995, 107, 2675 and 10417) that a fully isolated and characterised ruthenium(II)diphosphinediamine complex could be used as catalyst. High activity and high selectivity were generally associated with the use of chiral biaryl-phosphines (eg. Tol-BINAP and Xyl-BINAP) and diamines (eg. DPEN and DAIPEN) as ligands.
It has been reported that similar classes of Noyori-type ruthenium(II)(phosphine)2(diamine) complexes could catalyse the hydrogenation and asymmetric hydrogenation of activated (aromatic) imines (Abdur-Rashid et al., Organometallics, 2000, 20, 1655) or ruthenium(II)diphosphinediamine complexes (Abdur-Rashid et al., Presentations at The Canadian Society for Chemistry 83rd Conference and Exhibition, Calgary, Alberta, May 2000, and subsequently Abdur-Rashid et al., Organometallics, 2001, 21, 1047). Since these publications, Chirotech Technology Limited has also reported similar imine hydrogenation processes (Cobley et al. WO 02/08169 A1; Cobley at al. Adv. Synth. Catal. 2003, 345, 195) based on similar classes of complexes and imine substrates. It is noted that the reports of Abdur-Rashid et al. and Chirotech Technology Limited both relate to the use of Noyori-type ruthenium(II)-(phosphine)2(diamine) and ruthenium(II)diphosphinediamine complexes as catalysts for the reduction of activated imines of the Formula A shown below in which R represents an activating aryl group, R′ represents an alkyl group and R″ represents either an aryl or benzyl group.

In yet another publication (Abdur-Rashid et al., PCT/CA03/00689), the use of other similar Noyori-type ruthenium(II) complexes for the hydrogenation and asymmetric hydrogenation of unactivated imines has been reported, in which R and R′ in the Formula A simultaneously or independently represent alkyl or alkenyl substituents and R″ represents either an aryl, alkyl or alkenyl substituent. The imines described in this latter publication are inherently more difficult to reduce than the activated (aromatic) analogues reported by Chirotech.
To date, there are no reports in the literature which teach the use of such Noyori-type catalysts in hydrogenation processes for the reduction of a class of imines in which, in Formula A, R represents aryl; R′ represents cyclic, alkyl, alkenyl, alkynyl or aryl; and R″ represents cyclic or acyclic alkyl.
There is also a continuing demand for an enantioselective imine hydrogenation procedure that allows for the facile preparation of chiral primary amines in high yields and stereoselectivities. Such chiral primary amines are desired as valuable precursors, intermediates and end products in the pharmaceutical, agrochemical, fine chemical and material industries.